Project Summary/Abstract: Abnormal striatal circuitry is implicated in the pathogenesis of common neurodevelopmental conditions including autism spectrum disorder, tic disorder, attention-deficit/hyperactivity disorder, and obsessive-compulsive disorder. The motor, cognitive, and social impairments characteristic of these disorders often interfere with an individual?s ability to participate in activities of daily living. Despite the notion that defects in basal ganglia connectivity can drive these behavioral impairments, the genetic and molecular origins of both normal and pathologic neural circuits remain poorly understood, thereby limiting the rational development of therapeutics. Sox8 is a transcription factor whose loss results in impaired striatal direct pathway outgrowth. Sox8 mutant mice also appear to have defects in corticobulbar and corticospinal projections, despite that this gene is not expressed in these cortical neurons. Given that these two axon pathways form in close proximity within the internal capsule during early development, the anatomical defects present in Sox8 mutants thus suggest a novel role for the direct pathway in the guidance of descending cortical projections. The central hypothesis for this application is that direct pathway axons pioneer the forming internal capsule and guide descending corticobulbar and corticospinal axons through the diencephalon and midbrain. To test this hypothesis, Sox8 KO mice will be used as a tool to 1) interrogate the developmental requirement for the direct pathway in guiding the appropriate outgrowth of descending corticofugal axons and 2) elucidate the mechanism(s) by which it serves to guide them. Utilizing Sox8-EGFP (direct pathway) and Fezf2-TdTomato (corticofugal pathway) BAC transgenic reporters to trace these pathways throughout development, Aim 1 will focus on defining their developmental trajectories and determining their interdependence on one another for their proper formation. The proposed experiments in Aim 2 will focus on establishing in vitro assays to identify molecular regulators of direct and corticofugal pathway axon fasciculation and outgrowth. These assays will be used to evaluate a candidate factor, Tenm2, in mediating the observed axon defects apparent in Sox8 mutants. The successful completion of the aims outlined in this application will increase our understanding of how striatal defects can impact the appropriate formation of other major axon tracts and thereby contribute to the etiology of neurodevelopmental disorders